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Researchers at The University of Miami Miller School of Medicine Identify Gene Family Responsible for Regulating Nerve Regeneration

October 9, 2009 – Miami -Researchers at the University of Miami Miller School of Medicine have identified a family of genes that may control the ability of nerve cells to regenerate. The discovery of this gene family, as published in the October 9 issue of Science, is a big step forward for both regenerative science and neuroscience. The finding may one day lead to advances in diseases such as spinal cord injury, traumatic brain injury, glaucoma and optic nerve stroke, as well as other neurodegenerative diseases of the brain and spinal cord.

Long processes, called axons, transmit electrical impulses from one nerve cell to the next. If the axons of nerve cells in the brain or spinal cord are cut via injury or disease, electrical signals are not transmitted to their targets so important functions, such as control of movement or sensory information, are lost. It has been known for many years that neurons in the adult central nervous system have very poor regenerative ability, i.e., the cut or damaged axons cannot grow back to their targets. Interestingly, if axons are cut at a very young age, often they can regenerate quite well.

A team of scientists from The University of Miami’s The Miami Project to Cure Paralysis and Bascom Palmer Eye Institute have worked together to study this problem. Jeffrey Goldberg, M.D., Ph.D., assistant professor of ophthalmology explained “Neurons in the central nervous system grow normally during development and then they turn off their growth ability, such that they can’t reconnect properly in adults following injury or disease. Scientists have mostly studied the environment where the growth failure occurs, for example, the optic nerve. We were looking to see if there was a problem within the Retinal Ganglion Cells themselves, rather than in the environment.”

Members of the Vance Lemmon-John Bixby (LemBix) lab in The Miami Project have devoted the last several years to developing methods for testing hundreds of genes at a time for their ability to increase or decrease axon growth and to use automated microscopes to measure the changes of neurons growing in vitro. Dr. Goldberg’s Ph.D. student, Darcie L. Moore, used this approach to screen more than 100 genes looking to discover which would have a role in retinal ganglion cell (RGC) regeneration. She identified Krűppel-like factor-4 (KLF4) as a repressor of axon growth in RGCs and other central nervous system (CNS) neurons. KLF4 is expressed at low levels in the developing brain and higher levels in the adult brain. Amazingly, Dr. Murray Blackmore, a postdoctoral fellow in the LemBix lab, found a related gene (KLF6) in a similar screen on neurons from the cerebral cortex. He was studying genes that were found in motor neurons in the cortex that send axons to the spinal cord. In particular he looked at genes that changed during development. KLF6 is expressed at higher levels early in development, so it was exciting that both KLF4 and 6 showed changes in expression that correlated well with the loss of the ability of axons to regenerate.

The team expanded its studies to look at the whole KLF family, which includes 17 members and found that the entire KLF family may play significant roles in regulating regenerative ability of neurons in the brain. Importantly, when they tested the KLFs in combination, the KLFs that inhibit regeneration can prevent the regeneration promoting KLFs from having their positive effects. This finding has important implications for designing therapeutics that exploit the KLF family of genes for use in spinal cord and brain injury repair.